Dr. Buckwalter is a stroke neurologist and neurointensivist with training in genetics and molecular biology. She is interested in how the aged brain's response to injury affects repair and functional recovery. Aging is associated with less effective recovery from brain injury. The reasons for this decline are unknown, but a reduced capacity of the aging brain to form new neurons may be in part responsible. The applicant has generated preliminary data that demonstrate a marked inhibition of adult hippocampal neurogenesis by transforming growth factor beta-1 (TGF-beta1), a cytokine that is increased by aging and injury. This data, and the known effect of TGF-beta on the cell cycle, led her to propose the hypothesis that TGF-beta1 acts directly on neural progenitor cells to inhibit hippocampal neurogenesis. Thus, too much TGF-beta1 in the aging brain, and especially in the injured and aged brain, may inhibit neurogenesis. She will determine how TGF-beta1 affects the cell cycle and number of neural progenitor cells, how this translates into fewer new neurons, and whether the reversal of this effect leads to cognitive improvement. At the conclusion of these studies, we will have a significantly better understanding of the mechanism by which TGF-beta1 inhibits hippocampal neurogenesis. This application also details a carefully thought out career development plan that includes rich interaction with other laboratories at Stanford, exposure to seminars and scientific meetings, supervision of students and technicians, and classes in neuroscience and immunology. Dr. Buckwalter has strong institutional support that will allow her to focus on these studies with minimal distractions. This K08 Mentored Clinical Scientist Career Development Award will facilitate Dr. Buckwalter's transition from a neurologist with training in genetics to a physician scientist who is fully competent to investigate the injury response in aging in her own laboratory through independent, investigator-initiated funding. This research is directly related to public health because millions of people in the US are living with disability due to traumatic brain injury or stroke. Our data shows that elevated brain TGF-beta 1, which is seen in all these diseases, inhibits our ability to grow new neurons from cells in our own brains. We hope that the experiments in this application will help us to someday design strategies to grow new brain cells to replace those lost to these devastating diseases.